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Treating motor impairment in Parkinson’s disease

In 1967 Cotzias revolutionized the treatment of Parkinson’s disease by showing that levodopa could greatly improve the characteristic tremor, rigidity, bradykinesia and postural instability.

In the past four decades pharmacological progress has been spectacular, so now physicians and patients may choose among multiple options. Providence Center for Parkinson’s Disease uses some decision-making guides, informed by American Academy of Neurology practice parameters and by criteria developed by E.M. Cheng and colleagues, to measure quality of Parkinson’s care.

Drug options include:

Anticholinergics: trihexyphenidyl and others

L-DOPA: carbidopa/levodopa

Amantadine

Dopamine agonists: ropinirole, pramipexole, rotigotine, apomorphine

MAO-B inhibitors: selegiline, rasagiline

COMT inhibitors: entacapone, tolcapone

Early treatment

Assess for medication-induced parkinsonism »

Before starting treatment of idiopathic Parkinson’s disease, we must exclude medication-induced parkinsonism because it improves after stopping the offending drug.

The classic offenders, neuroleptic drugs such as chlorpromazine and haloperidol, are used less now than in the past. But we often see drug-induced parkinsonism from gastrointestinal drugs, such as metoclopramide (Reglan) or prochlorperazine (Compazine), and atypical antipsychotics such as olanzapine (Zyprexa) and risperidone (Risperdal).

Assess functional status »

Parkinson’s disease can interfere with many daily activities, such as speaking, swallowing, handwriting, dressing, using eating utensils, toileting, bathing, walking and turning in bed. We assess symptoms in these areas at each patient visit. Early in their illness, patients often continue their lives with minimal impairment. We have no proven therapy to slow the progressive neuronal destruction of the disease, so patients with early disease often do not need drug treatment.

As the disease progresses, some patients choose to be treated and others prefer to postpone medication. However, some forms of impairment, such as falls or choking, make treatment imperative.

Once patients are ready for treatment, they have many choices. If they are relatively young and tremor is the predominant problem, anticholinergic drugs, such as trihexyphenidyl, are a reasonable choice.

Anticholinergics are among the most effective drugs for tremor but are much less effective for rigidity, bradykinesia and gait impairment. They are inexpensive and easy to titrate. Typical side effects include dry mouth, constipation, urinary hesitancy, memory impairment and confusion. This makes them less suitable choices for older patients or those with cognitive impairment.

MAO-B inhibitors selegiline and rasagaline are another option for initial treatment. They have definite but modest benefit on motor function when used without levodopa. Interest in their use early in the disease has been prompted by suggestions that they may also have neuroprotective effects. For example, in a recent trial of rasagiline, using a delayed-start design, patients who received the rasagaline for a year were less parkinsonian than patients who received placebo for six months before taking rasagiline for the next six months.

Amantadine is also an option for mild Parkinson’s disease. The dose of 100 mg can be started once a day and adjusted as high as three times daily. The expense and side-effect profiles are modest but so is the potential value.

The most potent drug for Parkinson’s disease, levodopa, is now almost always given in combination, adding 25 mg of carbidopa to 100 mg of levodopa. Later in the illness other combinations of carbidopa/levodopa, 25 mg/250 mg or 10 mg/100 mg, are sometimes useful.

Other alternatives for dopaminerigic therapy are dopamine agonist drugs, such as ropinerole or pramipexole. The physician and patient need to collaborate to choose between levodopa and a dopamine agonist. Levodopa is more potent but has a shorter half-life. It requires dosing three times a day or more, and its use is often complicated by eventual wearing off or dyskinesias.

The dopamine agonists, however, are more prone to cause cognitive or behavioral side effects or excessive daytime sleepiness.

Titrate medications »

All medications used to treat Parkinson’s disease need careful adjustment to optimize effect and minimize side effects. We see most patients who are taking medication at least twice a year and maintain more frequent contact with phone calls or office visits whenever we change medications.

Time L-DOPA and diet »

The gastrointestinal absorption of L-DOPA can be blocked by dietary protein; however, some patients need to take L-DOPA with meals to minimize drug-induced nausea.

Patients need guidance on when to take L-DOPA in relation to meal times and on avoiding marked fluctuations in the protein content of their food.

Treating motor complications

Assess motor complications »

Patients with mild Parkinson’s can often be treated with levodopa three or four times a day or with a longer-acting dopamine agonist and have relatively stable improvement around the clock.

As the disease progresses, some patients, especially those taking levodopa, have fluctuating responses to medication, including gradual increases in motor impairment due to wearing off of medication effect or extra dyskinetic movements due to excessive medication effect.

Treat wearing off »

A number of pharmacological approaches can help mitigate wearing off. Options include:

Giving levodopa more often

Adding inhibitors of COMT (entacapone or tolcapone) or MAO-B (selegiline or rasagiline) so that these enzymes do not metabolize dopamine

Using dopamine agonists, which have a longer half-life than levodopa

A slow-release form of L-DOPA (Sinemet CR or carbidopa-levopoda ER) can prolong levodopa blood levels, but its clinical utility to treat wearing off is debated.

Use COMT inhibitors only if on levodopa »
Use entacapone before tolcapone »
Monitor liver function if on tolcapone »

COMT inhibitors prevent breakdown of levodopa. If taken with each dose of carbidopa-levodopa, they can prolong on-time and decrease off-time after each dose by about half an hour. These drugs do not have significant therapeutic effect if given without levodopa.

Entacapone has less potential for liver toxicity than tolcapone, so it is the first-choice COMT-inhibitor. It is also available in combination with carbidopa-levodopa (as Stalevo) to facilitate patient adherence.

However, tolcapone is the more powerful COMT-inhibitor and will sometimes be effective for patients who have not responded to entacapone. When patients are taking tolcapone, they should have regular liver function tests to monitor for hepatic toxicity.

Manage dyskinesias »

Patients on levodopa are more likely than patients on dopamine agonists to develop drug-induced dyskinesia. The dyskinesias typically appear after a few years of levodopa treatment; the most common pattern is for dyskinesias appear when levodopa blood levels are highest.

One approach is to lower the levodopa dose, but the result is often worsening of parkinsonian motor symptoms. Patients can be nearly oblivious to mild dyskinesias, in which case we may continue the current levodopa dose but avoid future dose increases. Amantadine is one drug that sometimes reduces dyskinesias without worsening parkinsonian motor impairment.

Choose patients for DBS »
Avoid DBS if contraindicated »

If patients are carefully selected, deep brain stimulation (DBS) can very effectively treat motor fluctuations, increasing the duration of medication effect, decreasing dyskinesia and decreasing the amount of medication taken.

An experienced surgical team can place the stimulating electrodes in the thalamus, internal globus palidus or subthalamic nucleus with low risk of direct trauma, hemorrhage or stroke.

The electrodes are usually placed bilaterally and connected with subcutaneous wires to the battery and controls, which are placed, like a cardiac pacemaker, in a subcutaneous pocket on the upper chest. Physicians can adjust the stimulator with a handheld device; optimal adjustment of the stimulator can require a number of physician visits after surgery.

The motor improvement after surgery is usually no better than the patient’s best response to levodopa, so patient selection usually includes examining patients with and without medication. Cognitive changes, dysarthria or dysphagia sometimes increase during deep brain stimulation. Patients with significant cognitive impairment are usually not selected for DBS.

Conclusion

We have many opportunities to improve the motor aspects of Parkinson’s disease. Patients and physicians need to work together to choose medications, adjust doses, and deal with side effects. In addition, patients with Parkinson’s disease also have many non-motor impairments, which I will review in a future article.

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